Rift Valley fever virus (RVFV), a NIAID Category A pathogen, is a mosquito borne bunyavirus that can be spread by the aerosol route and cause hemorrhagic fever, encephalitis, or retinitis in infected humans. Vaccines represent the most effective means of controlling RVFV, however, no FDA approved RVFV vaccines exist. Therefore, our research group, which includes individuals at four different Universities with expertise in vaccine development, immune modulation, and RVFV biology, has developed and performed preliminary analysis of two RVFV vaccines based on either alphavirus replicon particles or DNA vaccines expressing secreted forms of the RVFV glycoproteins linked to the C3d molecular adjuvant. We propose to perform a detailed analysis of these vaccines both individually and in prime-boost combination to test their ability to induce protective anti-RVFV immune responses in a mouse model. This analysis will include head-to-head comparisons with two classical RVFV vaccine strategies based on inactivated RVFV and the live attenuated vaccine strain, MP-12. These studies, which will significantly enhance our understanding of anti-RVFV immune responses, are designed to identify vaccination strategies that will rapidly elicit durable anti-RVFV immunity, with the ultimate goal of developing a candidate RVFV vaccine that can be taken forward for human use. PUBLIC HEALTH RELEVANCE: Rift Valley fever virus (RVFV) is a NIAID Category A pathogen that represents an emerging disease threat to countries in both the developing and developed world. Though vaccination represents an important means of controlling RVFV, there are currently no FDA approved RVFV vaccines for human use. Therefore, we propose to test two promising vaccination strategies for their ability to rapidly elicit long lived protective anti-RVFV immune responses. In addition to the development of promising new RVFV vaccines, these studies will also fundamentally advance our overall understanding anti-RVFV antibody and T cells responses, which will be useful for moving these or other vaccines forward for human use.